Recently, an alternative pathway of neoplastic development has been identified in the colorectum which differs from the traditional adenoma-carcinoma pathway in that it is (a) associated with "serrated" precursor lesions and (b) driven by hypermethylation of multiple gene promoters and activating mutations in the BRAF proto-oncogene. At least 10-15% of CRC is likely to develop on the basis of a strong genetic predisposition. The two most well-characterized syndromes FAR and HNPCC both develop via the adenoma-carcinoma pathway and together account for approximately one-third of familial CRC. We have recently described several families in which there is evidence that the genetic predisposition to autosomal dominant CRC has its origins in the serrated pathway. This condition, Serrated Pathway Syndrome (SPS), and the related condition, Hyperplastic Polyposis (HPP), represent two syndromes in which BRAF mutation and methylation co-occur within serrated precursor lesions. The primary aim of this proposal is to identify the gene or genes which predispose to SPS and HPP. We will achieve this by carrying out a linkage study and fine-mapping procedure of well-characterised families with serrated neoplasia from Australasia, USA and Canada, supplemented and extended by candidate gene analysis, and expression profiling of normal tissue. The potential key outcome of this proposal will be the definition of the underlying genetic predisposition to develop serrated neoplasia. Currently, such families are unable to be offered presymptomatic testing. Recognition of this syndrome will allow families to be more definitively monitored for the lesions that act as precursors to their CRC, thereby preventing potential deaths. Presymptomatic testing of germline DNA will target screening to those individuals most at risk for developing colorectal cancer. Knowledge gained from this project will lead to a greater understanding of the disease mechanism, the opportunity for prevention (both chemo-prevention and screening endoscopy) and the development of novel treatment modalities. LAY DESCRIPTION: Colorectal cancer was once believed to develop only from a certain kind of polyp in the colon called the adenoma. However, recently another type of polyp called the hyperplastic polyp was found to also be capable of producing a cancer. In this proposal, we will explore the notion that the predisposition to form hyperplastic polyps may be inherited in families. [unreadable] [unreadable] [unreadable] [unreadable]